羧甲基壳聚糖局部医药用膜材料的研制及性能评价
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摘要
本文拟从设计出优良的牙周局部给药体系出发,采用先进的高分子材料加工工艺,复合羧甲基壳聚糖(CMCS)和聚乙烯醇(PVA)材料制备出CMCS/PVA共混膜和Cs2Ms-PVA多元结构微球嵌膜体系,研究两种膜材料的药剂学及生物学方面的特性,重点考察了羧甲基壳聚糖膜体系作为牙周局部药剂材料的潜力。现将实验过程及结果报道如下:
通过碱化壳聚糖和氯乙酸的取代反映,制备了两组不同规格的羧甲基壳聚糖样品,随后采用红外和核磁技术刻画了制备的羧甲基壳聚糖样品,电位滴定方法分析了样品分子上羧基和氨基的解离情况,特别是研究了内在因素(Ds和Dd)和外在因素(离子强度及pH)对可电离基团解离系数的影响。其结果表明,羧甲基壳聚糖样品上的羧基和氨基在由酸至碱的滴定过程中,质子化的羧基和氨基历经了分别的去质子化过程。羧基和氨基的解离明显不同于CMC上羧基和CS上氨基的解离行为。表现为羧基pKa值随解离度呈现出先下降后平缓的解离趋势,对于此规律的解离趋势,可以用数学公式模拟出氨基解离曲线,进而可以考察而羧基固有pK的变化,也可以观测出各因素对羧基pK的影响,结果显示Ds和Dd的变化都轻微的改变了羧基的解离曲线;氨基pKa值在整个解离过程中表现为复杂的递增趋势,Ds对其解离影响明显。另外,离子强度增加总是表现出屏蔽氨基和羧基解离的效应。
使用机械共混的方法制备了一系列CMCS/PVA共混膜,并在共混膜中加载了奥硝唑药物,通过肉眼和电镜观察观察了共混膜的外观,考察了共混膜的溶胀和体外药物释放特性,同时研究了共混膜对大肠杆菌和金黄色葡萄球菌的抑制效果。结果表明共混膜透明均匀,但在微观下其相容性较差;高CMCS含量共混膜吸水剧烈,药物从中释放迅速,而高PVA含量的共混膜pH敏感性不强烈,抑菌性较差。
为了考察CMCS/PVA共混膜作为药物包膜的潜力,我们也研究了小分子药物透过共混膜的释放情况。同样采用共混的方法制备CMCS/PVA共混膜,SEM检测提高共混膜中CMCS含量将造成共混膜表面粗造,横断面结构疏松,当CMCS含量升高到膜总重的50%时,吸水状态的共混膜呈现出多孔泡沫微观状态。CMCS的添加使共混膜具有了pH敏感性,表现为溶胀度随pH的升高而增大,高CMCS含量的共混膜尤其如此。采用改进的静态通透装置,研究了小分子模型药物透过共混膜的扩散情况,研究表明药物透过共混膜的扩散呈现出0级的药物释放趋势,提高CMCS含量,降低膜厚度以及增大介质pH值,都能使药物透膜的扩散加快。因此推测共混膜对小分子药物屏蔽不仅仅遵循孔型渗透机制。
共混膜的体外血浆蛋白吸附是一种电性吸附为主导,疏水作用为辅助的吸附模式。当改变共混膜中CMCS含量,变动吸附蛋白类型,调整吸附介质(pH和离子强度)时,都会对膜上蛋白的静态平衡吸附量产生影响。总的来说,高CMCS含量膜的蛋白吸附量小,BSA比BFG更容易在膜上吸附,在偏酸环境中蛋白更易吸附,离子强度低的条件下蛋白更容易吸附。除了白蛋白及纤维蛋白原在膜上有吸附之外,共混膜还会对其它的血浆蛋白产生吸附。蛋白吸附模式表明了共混膜良好的生物相容性,甚至优于PVA膜。采用体内埋植的方法同样证明了共混膜优良的生物相容性,当共混膜埋植一定时间后,CMCS成分被机体溶解吸收,剩余PVA成分成为多孔蜂窝状微观结构。
加载奥硝唑的共混药膜可以作为局部治疗牙周病的释药体系,载药共混膜具有强烈的抗厌氧菌性能,对豚鼠皮肤和大鼠牙周粘膜无刺激、无毒性,采用大鼠牙周炎动物模型实验显示药物在牙周局部浓度能长时间的维持较高浓度。
我们设想一种新型的局部用药膜剂,该膜剂由载药微球分散包嵌在可溶性的外膜中构成。当用在局部位点时,外膜溶解,释放出载药微球,发挥药物特性。使用乳化交联的方法制备了羧甲基壳聚糖微球,同时在微球中加载了奥硝唑。载药微球的外观、粒经、药物包载量和包封率,以及体外药物释放速率都可以通过改变制备条件而加以控制。增加投料药材比可以增大药物包载量和减慢体外药物释放速率;而在制备时使用DMSO对药物助溶能够改善微球的外观,但是药物包载量降低,并且药物突释明显。综合考虑,使用不含DMSO的高载药微球分散在PVA膜中,形成一个多元结构复合膜。对于多元结构复合膜而言,外膜在接触水介质30 min时就开始溶解破碎,100 min时完全溶解释放载药微球,并能把微球封闭在局部。此性质有益于多元结构复合膜用在牙周局部。奥硝唑从微球和多元结构复合膜中释放表现出2级释放现象,在前两小时内为药物突释,紧随其后的一个缓慢释药过程。因此,可以通过改变微球或者多元结构复合膜的制备工艺达到调节药物释放速度的目的。
新颖的多元结构复合膜的设计目的是针对牙周炎的治疗,因此需要对其生物安全性进行评价。生物学评价针对多元结构复合膜的核心(羧甲基壳聚糖微球,Cs2Ms)。采用溶血实验、蛋白吸附实验、及大鼠体内埋植实验对核心微球进行了评价,同时使用壳聚糖微球和PVA外膜作对照。体外实验结果显示,羧甲基壳聚糖微球无溶血性,且蛋白吸附量较壳聚糖微球少,蛋白吸附能力较弱,表明了羧甲基壳聚糖微球更高的生物相容性;体内埋植实验显示,微球埋植导致的炎症程度要高于PVA膜的埋植,虽然无法从体内埋植炎症判断羧甲基壳聚糖微球同壳聚糖微球的生物相容性优劣,但是微球埋植炎症反应对机体造成的伤害不甚明显,大鼠存活良好;体内外羧甲基壳聚糖微球的降解速度明显要快于壳聚糖微球,体外浸泡和体内埋植都能造成羧甲基壳聚糖微球的快速溶蚀,而壳聚糖微球降解缓慢,最终我们确信较短体内滞留时间就能使羧甲基壳聚糖被机体完全吸收,因此,羧甲基壳聚糖微球作为多元结构复合膜的核心适合牙周局部释药的目的。
总之,能够使用羧甲基壳聚糖复合其它高分子材料设计出合理的牙周局部用药剂型。我们使用羧甲基壳聚糖所设计的两种膜材料在应用到牙周局部时仍有不完善之处,在其推广应用之前仍有很多工作要继续。
In order to design suitable localized drug films with carboxymethyl-chitosan (CMCS), we prepared two types of CMCS film systems by using high technologic process of polymer materials, one is CMCS/PVA blend films and the other is CMCS microspheres (Cs2Ms) in PVA film forming a multi-structure system (Cs2Ms-PVA). In the paper, the two CMCS film systems that used for localized delivering drug were prepared. The pharmaceutical and biological properties of the two film systems were characterized, and their feasibilities for using as periodontal treatments were investigated. The results were reported as follow:
Several carboxymethyl-chitosan (CMCS) samples with different deacetylation degree (Dd) and/or substituent degree (Ds) were prepared from the carboxymethylation reaction of chitosan under soft conditions. The products were dissolved in standard HCl aqueous solution (0.1 M) to carry out potentiometric titration by using NaOH as titrating solution at different ionic strengths. Then the dissociation behaviors of protonated carboxyl and amine groups of CMCS were investigated under their degree of dissociation (α) and protonation constant (pKa) had been calculated. Moreover, influence of the intrinsic parameters (e.g. Dd and Ds) and extrinsic parameters (e.g. pH and ionic strength) on the dissociation behavior of CMCS were also considered in this paper. As a result, dissociations of carboxyl and amine on CMCS exhibited unusual behaviors in comparison with carboxyl on carboxymethyl-cellulose and amine groups on chitosan, respectively. The pKa values of carboxyl declined slightly at early dissociation stage but subsequently maintained constant. For that, we obtained the modeling equations by means of mathematic simulation. In contrast, the pKa of ammonium increased with its dissociation degree (αn) despite that there was an inflexed change on itsαn-pKa curve. The potentiometric behavior of carboxyl was hardly affected by variation of Dd or Ds. However, the intrinsic parameters (Dd and Ds) played more important role on dissociations of ammonium on CMCS. The ionic strength of media could bring screening effect on dissociaciation of both sorts of ionizable groups on CMCS. With increasing the ionic strength of media, screening effect on dissociations increased significantly. The distinguishable films composed of PVA and CMCS were prepared by
blending/casting method, and loaded with ornidazole as local drug delivery system. In vitro test, the blend films showed pH-depended swelling behavior and seemly drug release action, and also exhibited a little antibacterial activity for E.coil and S.aureus strains. Those characteristics of CMCS/PVA blend films were controlled by the weight ratio of CMCS and PVA in the blended films. Increasing the content of PVA in blended films reduced the swelling ratio and decelerated the drug release. However, increasing the content of CMCS would enhance the antibacterial activity.
A background for study CMCS/PVA blend film was the intended use of polymer films as coating material in a site-specific drug delivery system. The surface morphology of compact dried films and swollen blend films were detected using scanning electron microscopy. Roughness image was shown on the surface of high CMCS content blend films. The structure of 50%C films (i.e. content of CMCS in the blend was 50%) became loosen and porous after adsorbing water. Blending PVA with CMCS also brought the coating films with some pH-sensitive swelling properties. Low swelling degree was found at acidic condition, but high swelling degree was found at high pH conditions. Permeation of model drugs through blend films was studied using a modified side-to-side static diffusion-vessels. The results showed that drugs permeation was affected by several impacts. Enhancement of the CMCS content in the blend film, decrease of the drugs’molecule weight, increase the pH of medium and rational attenuation of the film thickness would all accelerated the solutes permeating the blend coating films.
Bovine serum albumin (BSA) and bovine fibrinogen (BFG) were chose as representative plasma proteins to carry out adsorption test. Equilibrium adsorption amount of proteins onto the blends decreased with the increase of CMCS content in film matrix, and BSA was more easily adsorbed onto the films than BFG at the same conditions. The blend films also exhibited different trend for BSA and BFG adsorption when pH of the media changed, but maximum adsorption approximately occurred at the isoelectric point of proteins. Moreover, increasing the ionic strength would always decrease the adsorptions of protein onto the films. In animal experiments, it was found that incorporation of CMCS and PVA brought lower tissue reaction than pure PVA films as they were subcutaneously implanted in Wister rat. After two weeks subcutaneous implantation, surfaces of PVA became wrinkled and cracked, however, the blend implants exhibited alveolate porous microstructure.
The bioactivities of the blend film were also checked using anaerobic bacterial and some animal molds. This blend drug system was of no hemolysis, no toxicity to skin of Guinea pig and periodontium of Wister rat, and exhibited excellent antibacterial activity to ATCC 25586 and ATCC 25175. After embedding the 30%C blend drug films in the periodontum of rat model, the systems kept a good retention at the application site and maintained high drug concentration in long time (5 days) more extended the period in vitro (220 mins).
Carboxymethyl-chitosan microspheres (Cs2Ms) were prepared by a method of emulsification combined with two-step solidification and loaded ornidazole as model drug. The ornidazole loaded Cs2Ms were incorporated into PVA film to form a multi-structure drug system (Cs2Ms-PVA) for feasibly releasing drug in local site. The appearance, particle size, drug loading and encapsulation efficiency, and drug release profiles of Cs2Ms could be tailored in the preparation. Appropriate enhancement of drug amount in the microsphere would bring optimum effect on drug loading percentage and release profile. The use of dimethylsulfoxide (DMSO) could produce spherical spheres with smooth surface and small size, but depress the drug loading and encapsulation efficiency and hasten the burst drug release. For the multi-structure carrier materials, the outer PVA film rapidly breaks up to pieces after about 30 min of placement in water and then entirely dissolved. Drug release from the multi-structure carriers was a little faster than that from the pure Cs2Ms. Ornidazole release from the carriers performed a burst release in the initial 2 hours then followed a gradual release. It could be achieved the controlled release pattern of ornidazole by dispersing the well prepared Cs2Ms into PVA film.
As core parts of the novel formulation of Cs2Ms-PVA, chitosan-based microsphere was prepared form chitosan and/or carboxymethyl-chitosan (CM-chitosan) by using water in oil emulsification method. Then basic in vitro and in vivo experiments focusing on biocompatibility and biodegradability of the chitosan-based microspheres were carried out to evaluate the feasibility of the novel film formulation. In vitro tests, besides having no hemolysis, CM-chitosan microsphere (Cs2Ms) have adsorbed little proteins on their surfaces. Moreover, plasma proteins adsorbed on Cs2Ms, most of which can easily desorbed, are much less than that adsorbed on Cs1Ms. This indicates that Cs2Ms perhaps has better biocompatibility than Cs1Ms. In vivo tests, subcutaneous implantation of Cs1Ms and Cs2Ms in rat was carried out to investigate the host tissue inflammatory response and biodegradability of the microspheres. Implantations of Cs1Ms and Cs2Ms induced a littlie more severe inflammation when compared with the implantation of PVA film. However, the difference on in vivo biocompatibility between Cs1Ms and Cs2Ms could not be confirmed by the implantation model used in our experiments. Both Cs1Ms and Cs2Ms had suffered bioerosion when they were subcutaneously implanted. The hard and compact matrixes of Cs1Ms were degraded very slowly, and only some trifling degradation had been found until 4 weeks of implantation. In contrast, Cs2Ms is soft and more hydrophilic, and can be quickly degraded in a form of diffluence by the physiological circumstance. All these results suggested that Cs2Ms had better potentials used as core parts of the novel designed film dosage in the future developments.
Based on the above considerations, we incline to design the novel periodontal localized drug delivery system with carboxymethyl-chitosan in despite that there were some limits on the development of the two film dosages based on in vivo or in vitro findings.
通过碱化壳聚糖和氯乙酸的取代反映,制备了两组不同规格的羧甲基壳聚糖样品,随后采用红外和核磁技术刻画了制备的羧甲基壳聚糖样品,电位滴定方法分析了样品分子上羧基和氨基的解离情况,特别是研究了内在因素(Ds和Dd)和外在因素(离子强度及pH)对可电离基团解离系数的影响。其结果表明,羧甲基壳聚糖样品上的羧基和氨基在由酸至碱的滴定过程中,质子化的羧基和氨基历经了分别的去质子化过程。羧基和氨基的解离明显不同于CMC上羧基和CS上氨基的解离行为。表现为羧基pKa值随解离度呈现出先下降后平缓的解离趋势,对于此规律的解离趋势,可以用数学公式模拟出氨基解离曲线,进而可以考察而羧基固有pK的变化,也可以观测出各因素对羧基pK的影响,结果显示Ds和Dd的变化都轻微的改变了羧基的解离曲线;氨基pKa值在整个解离过程中表现为复杂的递增趋势,Ds对其解离影响明显。另外,离子强度增加总是表现出屏蔽氨基和羧基解离的效应。
使用机械共混的方法制备了一系列CMCS/PVA共混膜,并在共混膜中加载了奥硝唑药物,通过肉眼和电镜观察观察了共混膜的外观,考察了共混膜的溶胀和体外药物释放特性,同时研究了共混膜对大肠杆菌和金黄色葡萄球菌的抑制效果。结果表明共混膜透明均匀,但在微观下其相容性较差;高CMCS含量共混膜吸水剧烈,药物从中释放迅速,而高PVA含量的共混膜pH敏感性不强烈,抑菌性较差。
为了考察CMCS/PVA共混膜作为药物包膜的潜力,我们也研究了小分子药物透过共混膜的释放情况。同样采用共混的方法制备CMCS/PVA共混膜,SEM检测提高共混膜中CMCS含量将造成共混膜表面粗造,横断面结构疏松,当CMCS含量升高到膜总重的50%时,吸水状态的共混膜呈现出多孔泡沫微观状态。CMCS的添加使共混膜具有了pH敏感性,表现为溶胀度随pH的升高而增大,高CMCS含量的共混膜尤其如此。采用改进的静态通透装置,研究了小分子模型药物透过共混膜的扩散情况,研究表明药物透过共混膜的扩散呈现出0级的药物释放趋势,提高CMCS含量,降低膜厚度以及增大介质pH值,都能使药物透膜的扩散加快。因此推测共混膜对小分子药物屏蔽不仅仅遵循孔型渗透机制。
共混膜的体外血浆蛋白吸附是一种电性吸附为主导,疏水作用为辅助的吸附模式。当改变共混膜中CMCS含量,变动吸附蛋白类型,调整吸附介质(pH和离子强度)时,都会对膜上蛋白的静态平衡吸附量产生影响。总的来说,高CMCS含量膜的蛋白吸附量小,BSA比BFG更容易在膜上吸附,在偏酸环境中蛋白更易吸附,离子强度低的条件下蛋白更容易吸附。除了白蛋白及纤维蛋白原在膜上有吸附之外,共混膜还会对其它的血浆蛋白产生吸附。蛋白吸附模式表明了共混膜良好的生物相容性,甚至优于PVA膜。采用体内埋植的方法同样证明了共混膜优良的生物相容性,当共混膜埋植一定时间后,CMCS成分被机体溶解吸收,剩余PVA成分成为多孔蜂窝状微观结构。
加载奥硝唑的共混药膜可以作为局部治疗牙周病的释药体系,载药共混膜具有强烈的抗厌氧菌性能,对豚鼠皮肤和大鼠牙周粘膜无刺激、无毒性,采用大鼠牙周炎动物模型实验显示药物在牙周局部浓度能长时间的维持较高浓度。
我们设想一种新型的局部用药膜剂,该膜剂由载药微球分散包嵌在可溶性的外膜中构成。当用在局部位点时,外膜溶解,释放出载药微球,发挥药物特性。使用乳化交联的方法制备了羧甲基壳聚糖微球,同时在微球中加载了奥硝唑。载药微球的外观、粒经、药物包载量和包封率,以及体外药物释放速率都可以通过改变制备条件而加以控制。增加投料药材比可以增大药物包载量和减慢体外药物释放速率;而在制备时使用DMSO对药物助溶能够改善微球的外观,但是药物包载量降低,并且药物突释明显。综合考虑,使用不含DMSO的高载药微球分散在PVA膜中,形成一个多元结构复合膜。对于多元结构复合膜而言,外膜在接触水介质30 min时就开始溶解破碎,100 min时完全溶解释放载药微球,并能把微球封闭在局部。此性质有益于多元结构复合膜用在牙周局部。奥硝唑从微球和多元结构复合膜中释放表现出2级释放现象,在前两小时内为药物突释,紧随其后的一个缓慢释药过程。因此,可以通过改变微球或者多元结构复合膜的制备工艺达到调节药物释放速度的目的。
新颖的多元结构复合膜的设计目的是针对牙周炎的治疗,因此需要对其生物安全性进行评价。生物学评价针对多元结构复合膜的核心(羧甲基壳聚糖微球,Cs2Ms)。采用溶血实验、蛋白吸附实验、及大鼠体内埋植实验对核心微球进行了评价,同时使用壳聚糖微球和PVA外膜作对照。体外实验结果显示,羧甲基壳聚糖微球无溶血性,且蛋白吸附量较壳聚糖微球少,蛋白吸附能力较弱,表明了羧甲基壳聚糖微球更高的生物相容性;体内埋植实验显示,微球埋植导致的炎症程度要高于PVA膜的埋植,虽然无法从体内埋植炎症判断羧甲基壳聚糖微球同壳聚糖微球的生物相容性优劣,但是微球埋植炎症反应对机体造成的伤害不甚明显,大鼠存活良好;体内外羧甲基壳聚糖微球的降解速度明显要快于壳聚糖微球,体外浸泡和体内埋植都能造成羧甲基壳聚糖微球的快速溶蚀,而壳聚糖微球降解缓慢,最终我们确信较短体内滞留时间就能使羧甲基壳聚糖被机体完全吸收,因此,羧甲基壳聚糖微球作为多元结构复合膜的核心适合牙周局部释药的目的。
总之,能够使用羧甲基壳聚糖复合其它高分子材料设计出合理的牙周局部用药剂型。我们使用羧甲基壳聚糖所设计的两种膜材料在应用到牙周局部时仍有不完善之处,在其推广应用之前仍有很多工作要继续。
In order to design suitable localized drug films with carboxymethyl-chitosan (CMCS), we prepared two types of CMCS film systems by using high technologic process of polymer materials, one is CMCS/PVA blend films and the other is CMCS microspheres (Cs2Ms) in PVA film forming a multi-structure system (Cs2Ms-PVA). In the paper, the two CMCS film systems that used for localized delivering drug were prepared. The pharmaceutical and biological properties of the two film systems were characterized, and their feasibilities for using as periodontal treatments were investigated. The results were reported as follow:
Several carboxymethyl-chitosan (CMCS) samples with different deacetylation degree (Dd) and/or substituent degree (Ds) were prepared from the carboxymethylation reaction of chitosan under soft conditions. The products were dissolved in standard HCl aqueous solution (0.1 M) to carry out potentiometric titration by using NaOH as titrating solution at different ionic strengths. Then the dissociation behaviors of protonated carboxyl and amine groups of CMCS were investigated under their degree of dissociation (α) and protonation constant (pKa) had been calculated. Moreover, influence of the intrinsic parameters (e.g. Dd and Ds) and extrinsic parameters (e.g. pH and ionic strength) on the dissociation behavior of CMCS were also considered in this paper. As a result, dissociations of carboxyl and amine on CMCS exhibited unusual behaviors in comparison with carboxyl on carboxymethyl-cellulose and amine groups on chitosan, respectively. The pKa values of carboxyl declined slightly at early dissociation stage but subsequently maintained constant. For that, we obtained the modeling equations by means of mathematic simulation. In contrast, the pKa of ammonium increased with its dissociation degree (αn) despite that there was an inflexed change on itsαn-pKa curve. The potentiometric behavior of carboxyl was hardly affected by variation of Dd or Ds. However, the intrinsic parameters (Dd and Ds) played more important role on dissociations of ammonium on CMCS. The ionic strength of media could bring screening effect on dissociaciation of both sorts of ionizable groups on CMCS. With increasing the ionic strength of media, screening effect on dissociations increased significantly. The distinguishable films composed of PVA and CMCS were prepared by
blending/casting method, and loaded with ornidazole as local drug delivery system. In vitro test, the blend films showed pH-depended swelling behavior and seemly drug release action, and also exhibited a little antibacterial activity for E.coil and S.aureus strains. Those characteristics of CMCS/PVA blend films were controlled by the weight ratio of CMCS and PVA in the blended films. Increasing the content of PVA in blended films reduced the swelling ratio and decelerated the drug release. However, increasing the content of CMCS would enhance the antibacterial activity.
A background for study CMCS/PVA blend film was the intended use of polymer films as coating material in a site-specific drug delivery system. The surface morphology of compact dried films and swollen blend films were detected using scanning electron microscopy. Roughness image was shown on the surface of high CMCS content blend films. The structure of 50%C films (i.e. content of CMCS in the blend was 50%) became loosen and porous after adsorbing water. Blending PVA with CMCS also brought the coating films with some pH-sensitive swelling properties. Low swelling degree was found at acidic condition, but high swelling degree was found at high pH conditions. Permeation of model drugs through blend films was studied using a modified side-to-side static diffusion-vessels. The results showed that drugs permeation was affected by several impacts. Enhancement of the CMCS content in the blend film, decrease of the drugs’molecule weight, increase the pH of medium and rational attenuation of the film thickness would all accelerated the solutes permeating the blend coating films.
Bovine serum albumin (BSA) and bovine fibrinogen (BFG) were chose as representative plasma proteins to carry out adsorption test. Equilibrium adsorption amount of proteins onto the blends decreased with the increase of CMCS content in film matrix, and BSA was more easily adsorbed onto the films than BFG at the same conditions. The blend films also exhibited different trend for BSA and BFG adsorption when pH of the media changed, but maximum adsorption approximately occurred at the isoelectric point of proteins. Moreover, increasing the ionic strength would always decrease the adsorptions of protein onto the films. In animal experiments, it was found that incorporation of CMCS and PVA brought lower tissue reaction than pure PVA films as they were subcutaneously implanted in Wister rat. After two weeks subcutaneous implantation, surfaces of PVA became wrinkled and cracked, however, the blend implants exhibited alveolate porous microstructure.
The bioactivities of the blend film were also checked using anaerobic bacterial and some animal molds. This blend drug system was of no hemolysis, no toxicity to skin of Guinea pig and periodontium of Wister rat, and exhibited excellent antibacterial activity to ATCC 25586 and ATCC 25175. After embedding the 30%C blend drug films in the periodontum of rat model, the systems kept a good retention at the application site and maintained high drug concentration in long time (5 days) more extended the period in vitro (220 mins).
Carboxymethyl-chitosan microspheres (Cs2Ms) were prepared by a method of emulsification combined with two-step solidification and loaded ornidazole as model drug. The ornidazole loaded Cs2Ms were incorporated into PVA film to form a multi-structure drug system (Cs2Ms-PVA) for feasibly releasing drug in local site. The appearance, particle size, drug loading and encapsulation efficiency, and drug release profiles of Cs2Ms could be tailored in the preparation. Appropriate enhancement of drug amount in the microsphere would bring optimum effect on drug loading percentage and release profile. The use of dimethylsulfoxide (DMSO) could produce spherical spheres with smooth surface and small size, but depress the drug loading and encapsulation efficiency and hasten the burst drug release. For the multi-structure carrier materials, the outer PVA film rapidly breaks up to pieces after about 30 min of placement in water and then entirely dissolved. Drug release from the multi-structure carriers was a little faster than that from the pure Cs2Ms. Ornidazole release from the carriers performed a burst release in the initial 2 hours then followed a gradual release. It could be achieved the controlled release pattern of ornidazole by dispersing the well prepared Cs2Ms into PVA film.
As core parts of the novel formulation of Cs2Ms-PVA, chitosan-based microsphere was prepared form chitosan and/or carboxymethyl-chitosan (CM-chitosan) by using water in oil emulsification method. Then basic in vitro and in vivo experiments focusing on biocompatibility and biodegradability of the chitosan-based microspheres were carried out to evaluate the feasibility of the novel film formulation. In vitro tests, besides having no hemolysis, CM-chitosan microsphere (Cs2Ms) have adsorbed little proteins on their surfaces. Moreover, plasma proteins adsorbed on Cs2Ms, most of which can easily desorbed, are much less than that adsorbed on Cs1Ms. This indicates that Cs2Ms perhaps has better biocompatibility than Cs1Ms. In vivo tests, subcutaneous implantation of Cs1Ms and Cs2Ms in rat was carried out to investigate the host tissue inflammatory response and biodegradability of the microspheres. Implantations of Cs1Ms and Cs2Ms induced a littlie more severe inflammation when compared with the implantation of PVA film. However, the difference on in vivo biocompatibility between Cs1Ms and Cs2Ms could not be confirmed by the implantation model used in our experiments. Both Cs1Ms and Cs2Ms had suffered bioerosion when they were subcutaneously implanted. The hard and compact matrixes of Cs1Ms were degraded very slowly, and only some trifling degradation had been found until 4 weeks of implantation. In contrast, Cs2Ms is soft and more hydrophilic, and can be quickly degraded in a form of diffluence by the physiological circumstance. All these results suggested that Cs2Ms had better potentials used as core parts of the novel designed film dosage in the future developments.
Based on the above considerations, we incline to design the novel periodontal localized drug delivery system with carboxymethyl-chitosan in despite that there were some limits on the development of the two film dosages based on in vivo or in vitro findings.
引文
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